Monitoring of NPM1 mutant (mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as MRD transcript level <1-2% with <1-log change between any 2 positive samples collected after the end of treatment (EOT). As the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received at least 2 cycles of intensive chemotherapy were included if NPM1mut MRD positive in the bone marrow at the EOT and not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year: either spontaneously achieving complete molecular remission (30%) or retaining low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow up). Forty percent met the criteria for MP-LCN. Pre-emptive salvage therapy was found to significantly prolong relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-ITD at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.

Cancer cell metabolism is increasingly recognised as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small molecule ironomycin (AM5) reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent non-redundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. Statement of SignificanceIronomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces mitochondrial outer membrane permeabilization through a different mechanism to BH3 mimetics and consequently combination therapy has marked synergy in cancers such as AML.

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